This is an application to establish a Silvio O. Conte Center for Neuroscience Research (CCNR) on GENETIC, PHYSIOLOGICAL, AND BEHAVIORAL STUDIES OF MEMORY. The long-term objective of the Center is to elucidate the molecular, cellular, and neuronal ensemble mechanisms of mammalian learning and memory. The CCNR attacks the problem at three levels. First, it seeks to understand the elementary mechanisms of synaptic plasticity in the hippocampus and neocortex, and how these are developmentally and regionally regulated. Second, the Center seeks to understand how neuronal activity in the hippocampus and neocortex represents information about the outside world, how this information is compared with previous experience, and how these representations are consolidated into long-term memory. Third, the Center seeks to connect the synaptic plasticity and the neuronal correlates of learning with behavioral measures of memory. The elementary mechanisms of synaptic plasticity will be studied by applying electrophysiological techniques to brain slices derived from the hippocampus and the visual and inferotemporal cortices of mice with several specific spatially targeted genetic lesions (knockout mice). A novel electrophysiological technique that permits the analysis of single visualized synapses of cultured neurons will also be used for the analysis of these mice. In order to understand how neuronal activity represents learned information, the Center will seek to identify alterations in the activity of neuronal ensembles in the hippocampus, inferotemporal cortex, and prefrontal cortex by applying the novel multiple tetrode recording techniques to monkeys or rodents that are undertaking various memory tasks. Finally, in order to connect synaptic plasticity and neuronal correlates of learning with behavioral measures of memory, the Center takes advantage of the new methods of regionally and temporally selective genetic disruptions in mice, some of which have already been developed in the Center (hippocampus CAI-selective) while others (neocortex and neocortical subregion-specific) are proposed to be developed as a core project. The proposed research is truly interdisciplinary covering molecular genetics of mice, electrophysiology of brain slices and cultured neurons from rats and mice, and multiple electrode recordings of monkeys, rats, and genetically engineered mice performing specific memory tasks. Six investigators from three institutions and the seventh investigator as a subcontractor, each possessing complimentary and well-recognized expertise and state of the art experimental technologies will join forces and collaborate extensively in the CCNR framework. The Center's research is highly relevant to mental health and illness because mnemonic impairments are a hallmark of aging and major neurological diseases such schizophrenia, Alzheimer's disease and Parkinson's disease.